Hypersensitivity is an immune response after exposure to an antigen. Hypersensitivity usually causes tissue damage. Typical hypersensitivity reactions are allergic rhinitis, allergic conjunctivitis, urticaria, pruritus, sinusitis, angioedema, and anaphylaxis. Antihistamines, normally classified as H.sub.1 receptor antagonists, are used for the prophylaxis and relief of symptoms of hypersensitivity reactions.
The term “antihistamine” is generally applied to Histamine H.sub.1 receptor antagonists. There are two types of antihistamines: first generation and second generation. The older antihistamines (first generation antihistamines) are associated with troublesome sedative and anti-muscarinic effects and are often called sedating antihistamines. These older antihistamines are distinguished from the newer (second generation) antihistamines which are essentially devoid of the sedative effect and are usually termed “non-sedating antihistamines”.
Both groups of antihistamines are commonly used. Many sedating antihistamines are widely used and are available over the counter. Typical first generation antihistamines include, without limitation, brompheniramine, chlorpheniramine, dexbrompheniramine, dexchlorpheniramine, carbinoxamine, clemastine, diphenhydramine, pyrilamine, tripelennamine, tripolidine, methdilazine, bromodiphenhydramine, promethazine, azatadine, cyproheptadine, diphenylpyraline, doxylamine, trimeprazine, phenindamine, hydroxyzine, ketotifen, tazifylline, meclazine, setastine, oxatomide, levocarbastine, lodoxamide, pheniramine, propiomazine, emedastine, flunarizine, meclozine, mefenidramine, methylsulfate and mepyramine.
Typical second generation antihistamines include, without limitation, fexofenadine, loratadine, descarboethoxyloratadine, norastemizole, desmethylastemizole, cetirizine, acrivastine, ketotifen, temelastine, ebastine, epinastine, mizolastine, and setastine, astemizole, levocetirizine, rupatadine, mizolastin, noberastine and mequitazine. Cetirizine, in spite of being a second generation antihistamine, has a low to moderate sedative effect.
The sedative effect of the sedating antihistamines can range from slight drowsiness to deep sleep. Daytime sedation can be a problem especially for those who drive or who operate machinery. In view of these problems with sedative antihistamines, non-sedative antihistamines have been developed. This group of compounds has little or no sedative effect and has replaced the first generation antihistamines, especially for daytime use. The major disadvantage of the non-sedating antihistamines is the occurrence of drug interactions and hazardous ventricular arrhythmias which has led to the withdrawal of two non-sedating antihistamines from the market.
Although the non-sedating antihistamines have been widely used for daytime control of allergies, the sedative effect of sedating antihistamines may be preferred by patients who suffer from insomnia or by patients who need a good night sleep. It may be especially advantageous to administer a sedating antihistamine in combination with a decongestant, such as phenylephrine, since decongestants such as phenylephrine often stimulate nervousness and anxiety in a patient. Thus, distinct advantages can be found in the use of “first generation antihistamines” and “second generation antihistamines.”
Some antihistamines have a long duration of action, either directly or via long-lived active metabolites. These antihistamines, upon repeated administration (for example, daily), build up in the blood stream to provide a relatively constant steady state level of antihistamine effect at all times during the day and night. The table below shows the elimination half-life of some common non-sedating H1 antihistamines:
TABLE 1Elimination Half-Life of Non-Sedating H1 AntihistaminesDrug (Active Metabolite)Elimination half-life (hours)Acrivastine1.4-2.1Astemizole20-30Desmethylastemizole290Ceterizine 7-10Ebastine13-16Fexofenadine11-15Loratidine7.8-11 Descarboethoxyloratidine17.3-24  Mizolazine 8-13
When the non-sedating antihistamine, or its metabolite, has a long half life (for example, the Loratadine metabolite Descarboethoxyloratadine), plasma levels reach a steady state after repeated use and as a result there are minimal changes in Cmin and Cmax. In those cases where one daily dose of a non-sedating antihistamine provides 24 hour relief, a dose of a sedating antihistamine can be followed within a few hours, for example within the first eight hours after ingestion, preferably within the first six hours, and more preferably by the beginning of the release of the non-sedating antihistamine. At this point, the release of the sedating and non-sedating antihistamines are overlapping and as a result their effects are additive. The sedating antihistamine provides for a greater antihistamine efficacy and advantageous side effect profile (e.g. sedation). The non-sedating antihistamine provides for 24 hour antihistamine coverage due to its long half life and its lack of sedation as a side effect. The short delay of the non-sedating antihistamine remains important to ensure that the peak plasma level (Cmax) that occurs at dosing does not occur at the time the patient is attempting to fall asleep. The timing of the delayed release of the non-sedating antihistamine will depend on the duration of the antihistamine action of the sedating antihistamine.
When the long half-life antihistamine is a non-sedating antihistamine, a sedative can be used alone or in combination with a sedating antihistamine to induce sleep. Antidepressants, in low dosages, can have a sedative effect. Suitable antidepressants, which can be used alone or in combination with a sedating-antihistamine, include tricyclic/polycyclic antidepressants such as doxepin or selective serotonin reuptake inhibitors such as trazodone. Doxepin is a histamine H1-H2-receptor antagonist, and in doses ranging from 5-25 mg can cause side effects ranging from drowsiness to sedation. Trazodone, when used as an antidepressant, has a typical dosage range of 150-400 mg. However, Trazodone, when administered in sub-therapeutic doses of 12.5 mg to 25 mg, can cause side effects ranging from drowsiness to sedation. Additionally, anxiolytic and hypnotic drugs such as hydroxyzine or diazepam can produce effects ranging from pleasant drowsiness to direct sedation.
The combination of an antihistamine with a decongestant is well known. U.S. Pat. No. 5,314,697 to Kwan et al. discloses compositions that contain the non-sedating antihistamine loratadine and the decongestant pseudoephedrine. Such compositions contain loratadine in a film coating for immediate release and pseudoephedrine in a core surrounded by the film coating so that the pseudoephedrine is released over an extended period. However, Kwan does not describe a composition that contains both a sedating antihistamine and a non-sedating antihistamine.
One of the most common side effects of sedating antihistamines, depending on the specific drug and its dose, is central nervous system (CNS) depression, with effects varying from slight drowsiness to deep sleep. The sedating antihistamines can also cause dizziness and a lack of coordination. These sedative properties of the first generation antihistamines interfere with the normal functioning of patients suffering from allergies. These patients have to be alert and remain ambulatory throughout the day. Therefore the use of first generation antihistamines, in spite of their unique and useful antihistaminic properties, has been limited.
U.S. Pat. No. 6,114,346 to Harris et al. discloses compositions containing the non-sedating antihistamine desloratadine and which may further contain a decongestant including phenylephrine, pseudoephedrine, and phenylpropanolamine. Such compositions are administered to patients afflicted with upper airway passage allergic inflammation associated with allergic rhinitis to treat or prevent sleep disorder. However, Harris does not describe compositions containing both a sedating antihistamine and a non-sedating antihistamine or to use such a composition to inhibit the release of histamine throughout the day and night.
U.S. Pat. No. 6,051,585 to Weinstein et al. discloses compositions administered once a day in a single oral dosage, containing a decongestant and an antihistamine, for example a non-sedating antihistamine such as loratadine or fexofenadine. Weinstein, however, does not describe a composition that includes both a sedating antihistamine and a non-sedating antihistamine.
U.S. Pat. No. 6,086,914 to Weinstein et al. discloses antihistamine compositions that contain a non-sedating antihistamine as well as a specific anticholinergic agent. Preferred examples of specific anticholinergic agents include belladona extracts such as atropine and scopolamine. None of the anticholinergic agents disclosed in this reference, however, is itself a sedating antihistamine and therefore the compositions disclosed are “essentially non-sedating.”
U.S. Pat. No. 5,648,358 to Mitra discloses antihistamine compositions that may contain a mixture of one or more sedating antihistamines including clemastine fumarate as well as an additional sedating antihistamine and a non-sedating antihistamine such as loratidine. The compositions also contain caffeine. Mitra, however, does not disclose the delayed release of either the sedating antihistamine or the non-sedating antihistamine.
U.S. Pat. No. 5,827,852 to Russell broadly discloses coated pharmaceutical compositions that may include mixtures of active ingredients including sedating and non-sedating antihistamines. Once again there is no disclosure of the delayed release of either the sedating antihistamine or the non-sedating antihistamine.
U.S. Pat. No. 6,262,077 to Shih discloses compositions for treatment of asthma, allergic rhinitis and related disorders comprising in combination a leukotriene receptor antagonist with a neurokinin antagonist. No sedating effects are disclosed or discussed.
Nelson, J. Allergy & Clin. Immunology 112(4), S96-S100 October 203), “Prospects for antihistamines in the treatment of asthma”, describes improvement in asthma control with montelukast, a leukotriene receptor antagonist, by co-administration with loratidine, a non-sedating antihistamine. As described in the abstract, the combination is thought to minimize the sedating effects of high levels of even non-sedating antihistamines, by reducing the amount required. Nelson, however, does not describe compositions containing a sedating and non-sedating antihistamine.
It is therefore an object of the invention to provide a once daily oral dosage form which provides both sedating and non-sedating antihistamines for night and daytime histamine control.
It is an object of the invention to provide a once-daily oral dosage form for night and daytime histamine control which comprises a long-lasting non-sedating antihistamine and a sedating non-histamine substance.
It is an object of the invention to provide a once daily oral dosage form which provides both one or more sedating compounds, histamine and/or non-histamine, and at least one non-sedating antihistamine for night and daytime histamine control, the dosage form further comprising a leukotriene receptor antagonist for enhanced control of symptoms.
It is a further object of the invention to enable the use of a once-a-day treatment for the symptoms of histamine release which may act either by the inhibition of the release of histamine, or by the prevention of the action of released histamine, or by another method that relieves the symptoms of histamine release.
It is a further object of the invention to provide a composition that is administered to a patient once-a-day so as to improve the ease of administration and thus increase the rate of patient compliance.
It is a further object of the invention to provide a composition that is designed to be administered once a day, either in the morning or in the evening.